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. 2014 Oct;35(10):1285-92.
doi: 10.1038/aps.2014.64. Epub 2014 Aug 25.

Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

Yi Yang  1 , Wang Li  2 , Yang Liu  2 , Yan Li  2 , Ling Gao  3 , Jia-jun Zhao  4
Affiliations

Alpha-lipoic acid attenuates insulin resistance and improves glucose metabolism in high fat diet-fed mice

Yi Yang et al. Acta Pharmacol Sin. 2014 Oct.

Abstract

Aim: To investigate whether alpha-lipoic acid (ALA) could attenuate the insulin resistance and metabolic disorders in high fat diet-fed mice.

Methods: Male mice were fed a high fat diet (HFD) plus ALA (100 and 200 mg·kg(-1)·d(-1)) or HFD plus a positive control drug metformin (300 mg·kg(-1)·d(-1)) for 24 weeks. During the treatments, the relevant physiological and metabolic parameters of the mice were measured. After the mice were euthanized, blood samples and livers were collected. The expression of proteins and genes related to glucose metabolism in livers were analyzed by immunoblotting and real time-PCR.

Results: HFD induced non-alcoholic fatty liver disease (NAFLD) and abnormal physiological and metabolic parameters in the mice, which were dose-dependently attenuated by ALA. ALA also significantly reduced HFD-induced hyperglycemia and insulin resistance in HFD-fed mice. Furthermore, ALA significantly upregulated the glycolytic enzymes GCK, HK-1 and PK, and the glycogen synthesis enzyme GS, and downregulated the gluconeogenic enzymes PEPCK and G6Pase, thus decreased glucose production, and promoted glycogen synthesis and glucose utilization in livers. Moreover, ALA markedly increased PKB/Akt and GSK3β phosphorylation, and nuclear carbohydrate response element binding protein (ChREBP) expression in livers. Metformin produced similar effects as ALA in HFD-fed mice.

Conclusion: ALA is able to sustain glucose homeostasis and prevent the development of NAFLD in HFD-fed mice.

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Figures

Figure 1
Figure 1
Effect of ALA on histology analysis of liver tissue. (A) Representative hematoxylin and eosin (H&E) staining of a liver tissue sample (magnification 200×). (B) Liver sections of HFD-induced NAFLD were analyzed for steatosis and inflammation. bP<0.05 vs LFD. eP<0.05 vs HFD. (C) Representative periodic acid-Schiff (PAS) staining of liver tissue (magnification 200×).
Figure 2
Figure 2
Effect of ALA on physiological variables. (A) Body weight, (B) blood glucose and (C) food intake of the mice (n=8–10 per group) were examined every 3 weeks. (D) Energy intake of the mice (n=8–10 per group) was measured at 13 and 24 weeks. Mean±SEM. bP<0.05 vs LFD. eP<0.05 vs HFD.
Figure 3
Figure 3
Effect of ALA on glucose and insulin tolerance. (A and C) Intraperitoneal injection glucose tolerance test (IPGTT) of 13 or 24-week-old HFD-fed mice relative to ALA or metformin-administered mice (n=6 per group). Inset: The IPGTT is shown as the area under the curve (AUC). (B and D) Intraperitoneal injection insulin tolerance test (IPITT) of 13 or 24-week-old HFD-fed mice relative to ALA or metformin-administered mice (n=6 per group). Inset: The IPITT is shown as the AUC. Mean±SEM. bP<0.05 vs LFD. eP<0.05 vs HFD.
Figure 4
Figure 4
ALA induces the phosphorylation of Akt and GSK3β and nuclear ChREBP expression. (A) Phospho-Akt, (B) phospho-GSK3β and (C) nuclear ChREBP levels in the liver tissue samples were analyzed by Western blot. bP<0.05 vs LFD. eP<0.05 vs HFD.
Figure 5
Figure 5
ALA improves gene expression involved in glucose metabolism. (A–C) Glucokinase (GCK), pyruvate kinase (PK) and succinate dehydrogenase (SDH) activities of the liver. The data are expressed as the mean±SEM (n=6 per group). bP<0.05 vs LFD. eP<0.05 vs HFD. (D–F) Relative mRNA expression of GCK, hexokinase (HK1), PK, phosphoenolpyruvate kinase (PEPCK), glucose-6-phosphatase (G6Pase), glycogen synthase (GS) and citrate-synthase (CS). bP<0.05 vs LFD. eP<0.05 vs HFD. (G) Glycogen content of the liver (mg/g protein) and (H) glucose production (mmol/g protein). The data are expressed as the mean±SEM (n=8 per group). bP<0.05 vs LFD. eP<0.05 vs HFD.
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